tbuckley/cabot-search huggingface dataset:
Roles and implications of mRNA <i>N<sup>6</sup></i>‐methyladenosine in cancer
Authors: Lingxing Zeng, Xudong Huang, Jialiang Zhang, Dongxin Lin, Jian Zheng
Journal: Cancer Communications (2023)

Abstract RNA N 6 ‐methyladenosine modification is the most prevalent internal modification of eukaryotic RNAs and has emerged as a novel field of RNA epigenetics, garnering increased attention. To date, m 6 A modification has been shown to impact multiple RNA metabolic processes and play a vital role in numerous biological processes. Recent evidence suggests that aberrant m 6 A modification is a hallmark of cancer, and it plays a critical role in cancer development and progression through multiple mechanisms. Here, we review the biological functions of mRNA m 6 A modification in various types of cancers, with a particular focus on metabolic reprogramming, programmed cell death and tumor metastasis. Furthermore, we discuss the potential of targeting m 6 A modification or its regulatory proteins as a novel approach of cancer therapy and the progress of research on m 6 A modification in tumor immunity and immunotherapy. Finally, we summarize the development of different m 6 A detection methods and their advantages and disadvantages.
Loss of Macrophage mTORC2 Drives Atherosclerosis via FoxO1 and IL-1β Signaling
Authors: Xiangyu Zhang, Trent D. Evans, Sunny Chen, Ismail Sergin, Jeremiah Stitham, Se-Jin Jeong, Astrid Rodriguez-Velez, Yu-Sheng Yeh, Arick Park, In-Hyuk Jung, Abhinav Diwan, Joel D. Schilling, Oren Rom, Arif Yurdagul, Slava Epelman, Jaehyung Cho, Irfan J. Lodhi, Bettina Mittendorfer, Babak Razani
Journal: Circulation Research (2023)

The mTOR (mechanistic target of rapamycin) pathway is a complex signaling cascade that regulates cellular growth, proliferation, metabolism, and survival. Although activation of mTOR signaling has been linked to atherosclerosis, its direct role in lesion progression and in plaque macrophages remains poorly understood. We previously demonstrated that mTORC1 (mTOR complex 1) activation promotes atherogenesis through inhibition of autophagy and increased apoptosis in macrophages.
ESRRB Inhibits the TGFβ Signaling Pathway to Drive Cell Proliferation in Cervical Cancer
Authors: Qin-Shu Li, Peng-Sheng Zheng
Journal: Cancer Research (2023)

Abstract Estrogen-related receptor β (ESRRB) is a member of the orphan nuclear receptor family and mediates stem cell self-renewal and early embryonic development. Previous studies have also reported that ESRRB plays a role in the development and progression of breast cancer and prostate cancer. In this study, we observed that ESRRB was highly expressed in cervical cancer and was associated with disease progression. Knocking out ESRRB using CRISPR/Cas9 gene editing in cervical cancer cells induced cell-cycle arrest at the transition from the G0–G1 phase to the S phase, resulting in inhibition of cell proliferation in vitro and reduced tumor growth in vivo. Conversely, ectopic expression of ESRRB significantly promoted the proliferation of cervical cancer cells. ESRRB activated transcription of SMAD7, a TGFβ pathway inhibitor, which blocked phosphorylation and nuclear translocation of SMAD2/3 to the nucleus, thereby downregulating CDKN1A and upregulating CCNA2 and MYC. In turn, MYC transactivated ESRRB and upregulated SMAD7, thus forming a positive feedback loop with ESRRB. Together, these findings identify the tumor-promoting function of ESRRB in cervical cancer and reveal a mechanism by which ESRRB stimulates cell proliferation to promote cancer progression. Significance: The ESRRB/SMAD7/MYC-positive feedback loop inhibits TGFβ signaling to activate cell-cycle progression and promote proliferation in cervical cancer, thereby driving tumor growth.
Using Social Media Platforms for the Greater Good—The Case for Leveraging Social Media for Effective Public Health Messaging
Authors: Shikha Jain
Journal: JAMA Network Open (2023)

Nino Fijačko, MSc; Robert Greif, MD; Gregor Štiglic, PhD; Primož Kocbek, BSc; Benjamin S. Abella, MD, MPhil
Type 2 Diabetes Polygenic Score Predicts the Risk of Glucocorticoid-Induced Hyperglycemia in Patients Without Diabetes
Authors: Aaron J. Deutsch, Philip H. Schroeder, Ravi Mandla, Sarah Kang, Feyza Erenler, Josep M. Mercader, Miriam S. Udler, Jose C. Florez, Laura N. Brenner
Journal: Diabetes Care (2023)

OBJECTIVE To assess whether increased genetic risk of type 2 diabetes (T2D) is associated with the development of hyperglycemia after glucocorticoid treatment. RESEARCH DESIGN AND METHODS We performed a retrospective analysis of individuals with no diagnosis of diabetes who received a glucocorticoid dose of ≥10 mg prednisone. We analyzed the association between hyperglycemia and a T2D global extended polygenic score, which was constructed through a meta-analysis of two published genome-wide association studies. RESULTS Of 546 individuals who received glucocorticoids, 210 developed hyperglycemia and 336 did not. T2D polygenic score was significantly associated with glucocorticoid-induced hyperglycemia (odds ratio 1.4 per SD of polygenic score; P = 0.038). CONCLUSIONS Individuals with increased genetic risk of T2D have a higher risk of glucocorticoid-induced hyperglycemia. This finding offers a mechanism for risk stratification as part of a precision approach to medical treatment.
When I use a word . . . A short glossary of medical slang
Authors: Jeffrey K Aronson
Journal: BMJ (2023)

Slang is the subject of a myriad dictionaries and other books, going back to the 17th century. However, dictionaries devoted solely to medical slang are rare. Schmidt’s <i>Dictionary of Medical Slang</i> is the only general text of which I am aware, and it is out of date and long out of print.
Recent Evolution of a Maternally Acting Sex-Determining Supergene in a Fly with Single-Sex Broods
Authors: Robert B Baird, John M Urban, Andrew J Mongue, Kamil S Jaron, Christina N Hodson, Malte Grewoldt, Simon H Martin, Laura Ross
Journal: Molecular Biology and Evolution (2023)

Abstract Sex determination is a key developmental process, yet it is remarkably variable across the tree of life. The dipteran family Sciaridae exhibits one of the most unusual sex determination systems in which mothers control offspring sex through selective elimination of paternal X chromosomes. Whereas in some members of the family females produce mixed-sex broods, others such as the dark-winged fungus gnat Bradysia coprophila are monogenic, with females producing single-sex broods. Female-producing females were previously found to be heterozygous for a large X-linked paracentric inversion (X′), which is maternally inherited and absent from male-producing females. Here, we assembled and characterized the X′ sequence. As close sequence homology between the X and X′ made identification of the inversion challenging, we developed a k-mer–based approach to bin genomic reads before assembly. We confirmed that the inversion spans most of the X′ chromosome (∼55 Mb) and encodes ∼3,500 genes. Analysis of the divergence between the inversion and the homologous region of the X revealed that it originated very recently (&amp;lt;0.5 Ma). Surprisingly, we found that the X′ is more complex than previously thought and is likely to have undergone multiple rearrangements that have produced regions of varying ages, resembling a supergene composed of evolutionary strata. We found functional degradation of ∼7.3% of genes within the region of recombination suppression, but no evidence of accumulation of repetitive elements. Our findings provide an indication that sex-linked inversions are driving turnover of the strange sex determination system in this family of flies.
Reply to H. Onishi et al
Authors: Lakshmi Sandhya, Prasanth Ganesan
Journal: Journal of Clinical Oncology (2023)

We thank Onishi et al 1 for their interest in our article. 2The authors highlighted the problem of akathisia, a potential side effect of olanzapine.Studies of olanzapine as an antipsychotic agent (usual doses ranging from 10 to 20 mg once daily) have reported akathisia in 3%-16% of patients, 3 but these side effects are generally mild and rarely require treatment. 4Regarding akathisia in cancer patients, most of the reports are in patients with advanced malignancies, who often had associated psychiatric problems and were on medications known to have extrapyramidal symptoms (EPS). 5Among patients with newly diagnosed cancer, there are no data on the prevalence of akathisia.Akathisia occurs in 4.7% of patients receiving older-generation antiemetics (metoclopramide and prochlorperazine); however, these are rarely used as frontline agents in current practice.
FOLFOXIRI Plus Cetuximab or Bevacizumab as First-Line Treatment of <i>BRAF</i><sup>V600E</sup>-Mutant Metastatic Colorectal Cancer: The Randomized Phase II FIRE-4.5 (AIO KRK0116) Study
Authors: Sebastian Stintzing, Kathrin Heinrich, David Tougeron, Dominik Paul Modest, Ingo Schwaner, Jan Eucker, Rudolf Pihusch, Martina Stauch, Florian Kaiser, Christoph Kahl, Meinolf Karthaus, Christian Müller, Christof Burkart, Anke Reinacher-Schick, Stefan Kasper-Virchow, Ludwig Fischer von Weikersthal, Beate Krammer-Steiner, Gerald Wolfgang Prager, Julien Taieb, Volker Heinemann
Journal: Journal of Clinical Oncology (2023)

BRAFV600E mutation is associated with a poor outcome in metastatic colorectal cancer (mCRC). This clinical trial investigated the efficacy of triplet chemotherapy (fluorouracil, folinic acid, oxaliplatin, and irinotecan) combined with either cetuximab or bevacizumab in patients with previously untreated BRAFV600E-mutant mCRC.In this controlled, randomized, open-label phase II trial, 109 patients were randomly assigned, 107 of whom were included into the full analysis set (FAS). Patients were randomly assigned in a 2:1 ratio to receive either FOLFOXIRI plus cetuximab in the experimental arm (n = 72) or FOLFOXIRI plus bevacizumab in the control arm (n = 35). The primary end point was objective response rate (ORR) according to RECIST 1.1., evaluated in patients treated according to protocol (ATP population). Progression-free survival (PFS), overall survival (OS), toxicity, and feasibility were analyzed as secondary end points.Eighteen patients discontinued study treatment before the first tumor assessment, thus resulting in the ATP population of 89 patients. In these patients, ORR was 51% (30/59) in the cetuximab-based experimental arm and 67% (20/30) in the bevacizumab-based control arm (odds ratio, 1.93; 80% CI, 1.06 to 3.52; P = .92 [one-sided]). In the full analysis set, median PFS was significantly inferior in the experimental arm (6.7 months v 10.7 months; hazard ratio [HR], 1.89; P = .006). Median OS analyzed at an event rate of 64.5% showed a trend toward shorter survival in cetuximab-treated patients (12.9 months v 17.1 months; HR, 1.4; P = .20).To our knowledge, FIRE-4.5 is the first prospective and randomized study investigating first-line treatment of BRAFV600E-mutant mCRC. FOLFOXIRI plus cetuximab does not induce a higher ORR when compared with FOLFOXIRI plus bevacizumab in first-line treatment of BRAFV600E-mutant mCRC. Bevacizumab-based chemotherapy remains the preferable first-line treatment of patients with BRAFV600E-mutant mCRC.
An armed anti-immunoglobulin light chain nanobody protects mice against influenza A and B infections
Authors: Xin Liu, Thomas Balligand, Claire Carpenet, Hidde L. Ploegh
Journal: Science Immunology (2023)

The immune system eliminates pathogen intruders such as viruses and bacteria. To recruit immune effectors to virus-infected cells, we conjugated a small molecule, the influenza neuraminidase inhibitor zanamivir, to a nanobody that recognizes the kappa light chains of mouse immunoglobulins. This adduct was designed to achieve half-life extension of zanamivir through complex formation with the much-larger immunoglobulins in the circulation. The zanamivir moiety targets the adduct to virus-infected cells, whereas the anti-kappa component simultaneously delivers polyclonal immunoglobulins of indeterminate specificity and all isotypes. Activation of antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity promoted elimination of influenza neuraminidase-positive cells. A single dose of the conjugate protected mice against influenza A or B viruses and was effective even when given several days after infection with a lethal dose of virus. In the absence of circulating immunoglobulins, we observed no in vivo protection from the adduct. The type of conjugates described here may thus find application for both anti-influenza prophylaxis and therapy.
Associations between modest reductions in kidney function and adverse outcomes in young adults: retrospective, population based cohort study
Authors: Junayd Hussain, Nicholas Grubic, Ayub Akbari, Mark Canney, Meghan J Elliott, Pietro Ravani, Peter Tanuseputro, Edward G Clark, Gregory L Hundemer, Tim Ramsay, Navdeep Tangri, Greg A Knoll, Manish M Sood
Journal: BMJ (2023)

Abstract Objective To study age specific associations of modest reductions in estimated glomerular filtration rate (eGFR) with adverse outcomes. Design Retrospective, population based cohort study. Setting Linked healthcare administrative datasets in Ontario, Canada. Participants Adult residents (18-65 years) with at least one outpatient eGFR value (categorized in 10 unit increments from 50 mL/min/1.73m 2 to &gt;120 mL/min/1.73m 2 ), with no history of kidney disease. Main outcome measures eGFRs and hazard ratios of composite adverse outcome (all cause mortality, any cardiovascular event, and kidney failure) stratified by age (18-39 years, 40-49 years, and 50-65 years), and relative to age specific eGFR referents (100-110 mL/min/1.73m 2 ) for ages 18-39 years, 90-100 for 40-49 years, 80-90 for 50-65 years). Results From 1 January 2008 to 31 March 2021, among 8 703 871 adults (mean age 41.3 (standard deviation 13.6) years; mean index eGFR 104.2 mL/min/1.73m 2 (standard deviation 16.1); median follow-up 9.2 years (interquartile range 5.7-11.4)), modestly reduced eGFR measurements specific to age were recorded in 18.0% of those aged 18-39, 18.8% in those aged 40-49, and 17.0% in those aged 50-65. In comparison with age specific referents, adverse outcomes were consistently higher by hazard ratio and incidence for ages 18-39 compared with older groups across all eGFR categories. For modest reductions (eGFR 70-80 mL/min/1.73m 2 ), the hazard ratio for ages 18-39 years was 1.42 (95% confidence interval 1.35 to 1.49), 4.39 per 1000 person years; for ages 40-49 years was 1.13 (1.10 to 1.16), 9.61 per 1000 person years; and for ages 50-65 years was 1.08 (1.07 to 1.09), 23.4 per 1000 person years. Results persisted for each individual outcome and in many sensitivity analyses. Conclusions Modest eGFR reductions were consistently associated with higher rates of adverse outcomes. Higher relative hazards were most prominent and occurred as early as eGFR &lt;80 mL/min/1.73m 2 in younger adults, compared with older groups. These findings suggest a role for more frequent monitoring of kidney function in younger adults to identify individuals at risk to prevent chronic kidney disease and its complications.
A Case for Accelerating Standards to Achieve the FAIR Principles of Environmental Health Research Experimental Data
Authors: Rance Nault, Matthew C. Cave, Gabriele Ludewig, Hunter N.B. Moseley, Kelly G. Pennell, Tim Zacharewski
Journal: Environmental Health Perspectives (2023)

Background: Funding agencies, publishers, and other stakeholders are pushing environmental health science investigators to improve data sharing; to promote the findable, accessible, interoperable, and reusable (FAIR) principles; and to increase the rigor and reproducibility of the data collected. Accomplishing these goals will require significant cultural shifts surrounding data management and strategies to develop robust and reliable resources that bridge the technical challenges and gaps in expertise. Objective: In this commentary, we examine the current state of managing data and metadata—referred to collectively as (meta)data—in the experimental environmental health sciences. We introduce new tools and resources based on in&nbsp;vivo experiments to serve as examples for the broader field. Methods: We discuss previous and ongoing efforts to improve (meta)data collection and curation. These include global efforts by the Functional Genomics Data Society to develop metadata collection tools such as the Investigation, Study, Assay (ISA) framework, and the Center for Expanded Data Annotation and Retrieval. We also conduct a case study of in&nbsp;vivo data deposited in the Gene Expression Omnibus that demonstrates the current state of in&nbsp;vivo environmental health data and highlights the value of using the tools we propose to support data deposition. Discussion: The environmental health science community has played a key role in efforts to achieve the goals of the FAIR guiding principles and is well positioned to advance them further. We present a proposed framework to further promote these objectives and minimize the obstacles between data producers and data scientists to maximize the return on research investments. https://doi.org/10.1289/EHP11484
Leveraging the structures of the COVID-19 pandemic response for successful control of Ebola in Uganda
Authors: Henry Kyobe Bosa, M. Kariuki Njenga, Misaki Wayengera, Bruce Kirenga, Winters Muttamba, Jeanette Dawa, Robert F. Breiman, Eric Osoro, Isaac Ngere, Francis Omaswa, Samuel Okware, Richard Kabanda, Henry Mwebesa, Diana Atwine, Yonas Tegegn Woldemariam, Jane Ruth Aceng
Journal: Nature Medicine (2023)
Emerging insights into ethnic-specific <i>TP53</i> germline variants
Authors: Nicholas W Fischer, Yu-Heng Vivian Ma, Jean Gariépy
Journal: JNCI Journal of the National Cancer Institute (2023)

The recent expansion of human genomics repositories has facilitated the discovery of novel TP53 variants in populations of different ethnic origins. Interpreting TP53 variants is a major clinical challenge because they are functionally diverse, confer highly variable predisposition to cancer (including elusive low-penetrance alleles), and interact with genetic modifiers that alter tumor susceptibility. Here, we discuss how a cancer risk continuum may relate to germline TP53 mutations on the basis of our current review of genotype-phenotype studies and an integrative analysis combining functional and sequencing datasets. Our study reveals that each ancestry contains a distinct TP53 variant landscape defined by enriched ethnic-specific alleles. In particular, the discovery and characterization of suspected low-penetrance ethnic-specific variants with unique functional consequences, including P47S (African), G334R (Ashkenazi Jewish), and rs78378222 (Icelandic), may provide new insights in terms of managing cancer risk and the efficacy of therapy. Additionally, our analysis highlights infrequent variants linked to milder cancer phenotypes in various published reports that may be underdiagnosed and require further investigation, including D49H in East Asians and R181H in Europeans. Overall, the sequencing and projected functions of TP53 variants arising within ethnic populations and their interplay with modifiers, as well as the emergence of CRISPR screens and AI tools, are now rapidly improving our understanding of the cancer susceptibility spectrum, leading toward more accurate and personalized cancer risk assessments.
Early-Stage Lung Cancer: Using Circulating Tumor DNA to Get Personal
Authors: Christine M. Bestvina, Marina C. Garassino, Joel W. Neal, Heather A. Wakelee, Maximilian Diehn, Everett E. Vokes
Journal: Journal of Clinical Oncology (2023)

In recent years, we have seen groundbreaking progress in the treatment of early-stage nonsmall-cell lung cancer (NSCLC). 1 Neoadjuvant administration of the PD-1 inhibitor nivolumab with chemotherapy has been approved in patients with stage IB-IIIA disease, regardless of PD-L1 status. 2 Patients with stage II and III disease with a PD-L1 expression of ≥1% without driver mutations are eligible for the PD-L1 inhibitor atezolizumab after surgery and chemotherapy. 3atients with epidermal growth factor receptor (EGFR) mutations are now eligible for adjuvant therapy with osimertinib. 3
Respiratory complications in pediatric epidermal necrolysis: A retrospective study of 22 cases
Authors: Sophie Schmartz, Anne Welfringer-Morin, Muriel Le Bourgeois, Christophe Delacourt, Laureline Berteloot, Smail Hadj Rabia, Nathalia Bellon, Florence Moulin, Marie Pouletty, Nicolas Garcelon, Christine Bodemer, David Drummond
Journal: Journal of the American Academy of Dermatology (2023)
Interventions to address global inequity in diabetes: international progress
Authors: Ashby F Walker, Sian Graham, Louise Maple-Brown, Leonard E Egede, Jennifer A Campbell, Rebekah J Walker, Alisha N Wade, Jean Claude Mbanya, Judith A Long, Chittaranjan Yajnik, Nihal Thomas, Osagie Ebekozien, Oriyomi Odugbesan, Linda A DiMeglio, Shivani Agarwal
Journal: The Lancet (2023)
CATI: an efficient gene integration method for rodent and primate embryos by MMEJ suppression
Authors: Hongyu Chen, Xingchen Liu, Lanxin Li, Qingtong Tan, Shiyan Li, Li Li, Chunyang Li, Jiqiang Fu, Yong Lu, Yan Wang, Yidi Sun, Zhen-Ge Luo, Zongyang Lu, Qiang Sun, Zhen Liu
Journal: Genome biology (2023)

Abstract The efficiency of homology-directed repair (HDR) plays a crucial role in the development of animal models and gene therapy. We demonstrate that microhomology-mediated end-joining (MMEJ) constitutes a substantial proportion of DNA repair during CRISPR-mediated gene editing. Using CasRx to downregulate a key MMEJ factor, Polymerase Q ( Polq ), we improve the targeted integration efficiency of linearized DNA fragments and single-strand oligonucleotides (ssODN) in mouse embryos and offspring. CasRX-assisted targeted integration (CATI) also leads to substantial improvements in HDR efficiency during the CRISPR/Cas9 editing of monkey embryos. We present a promising tool for generating monkey models and developing gene therapies for clinical trials.
Analysis of Genome-Wide Mutational Dependence in Naturally Evolving <i>Mycobacterium tuberculosis</i> Populations
Authors: Anna G Green, Roger Vargas, Maximillian G Marin, Luca Freschi, Jiaqi Xie, Maha R Farhat
Journal: Molecular Biology and Evolution (2023)

Abstract Pathogenic microorganisms are in a perpetual struggle for survival in changing host environments, where host pressures necessitate changes in pathogen virulence, antibiotic resistance, or transmissibility. The genetic basis of phenotypic adaptation by pathogens is difficult to study in vivo. In this work, we develop a phylogenetic method to detect genetic dependencies that promote pathogen adaptation using 31,428 in vivo sampled Mycobacterium tuberculosis genomes, a globally prevalent bacterial pathogen with increasing levels of antibiotic resistance. We find that dependencies between mutations are enriched in antigenic and antibiotic resistance functions and discover 23 mutations that potentiate the development of antibiotic resistance. Between 11% and 92% of resistant strains harbor a dependent mutation acquired after a resistance-conferring variant. We demonstrate the pervasiveness of genetic dependency in adaptation of naturally evolving populations and the utility of the proposed computational approach.
Validation of myeloproliferative neoplasms associated risk factor RDW as predictor of thromboembolic complications in healthy individuals: analysis on 6849 participants of the SHIP-study
Authors: Kirsi Manz, Jeanette Bahr, Till Ittermann, Konstanze Döhner, Steffen Koschmieder, Tim H Brümmendorf, Martin Griesshammer, Matthias Nauck, Henry Völzke, Florian H Heidel
Journal: Leukemia (2023)